The present invention relates generally to medical apparatus and methods for determining in vivo the concentration of a chemical constituent in a body fluid using direct spectroscopic analysis of the fluid, and for removing or obviating actual or potential artifacts from measured spectral data.
In medicine, the measurement of the composition of blood and other body fluids is an often invaluable diagnostic tool and is used as a basis for the titration of medicines and the determination of therapy. Broadly speaking, there are two classes of devices used for the measurement of chemical constituents; chemical and optical. The chemical techniques are the most wide-spread and essentially all techniques used in the clinical laboratory are based on chemical techniques. Chemical techniques invariably rely upon the constituent reacting with a "reagent" and either an optical or electrical measurement of the reagent or the by-products of the reaction. Unfortunately, the present chemical techniques have many drawbacks, including the following drawbacks:
(1) Present commercially available instruments are invasive and require, generally, a drop of fluid to determine the chemical constituents.
(2) Present commercial instruments require a unique chemical reagent for the determination of each constituent. The reagents are generally expendable and need to be replaced, frequently after each measurement. Instrument maintenance is thus expensive and inconvenient, particularly for an implantable device.
(3) Implantable chemical sensors suffer from drift due to lack of stability of the reagents at body temperature over a period of time, and short lifetime due to biocompatibility problems.
(4) Chemical sensors generally consume the constituent they are to measure, affecting accuracy. In an implantable sensor, tissue reaction with the sensor invariably diminishes the supply of the constituents, causing a reduction in accuracy.
Optical techniques have been hailed by researchers as a means to overcome all the problems associated with chemical techniques, as they do not utilize a reagent or require any sort of chemical reaction and they do not require direct interaction of the sensor with the chemical constituent. Optical techniques can theoretically provide continuous, non-invasive, simultaneous determination of multiple chemical constituents. Despite the promise of optical techniques and the efforts by numerous groups throughout the world to perfect such techniques, optical techniques are rarely used in clinical medicine. The pulse oximeter and an instrument which measures percent of body fat are notable exceptions.
One sensor particularly sought by researchers has been a home use glucose sensor for insulin-dependent diabetics. Ideally, such a sensor would be non-invasive or permanently implantable, would provide a continuous or quasi-continuous means of measurement of blood glucose, and would be accurate over the physiological range of blood chemistry and other conditions and would require minimal patient intervention. There are reportedly over 60 groups throughout the world who are currently attempting to develop such at sensor, yet no group is known to be close to success. The rationale behind these efforts are the staggering cost of the complication of diabetes on both the patient and the health care system. Studies have shown that the complications of diabetes can be reduced significantly with tight control of blood sugar.
Diabetes is a major chronic disease, costing the United States between $90 and $110 billion annually in health care costs alone. Approximately 750,000 people in United States have insulin dependent diabetes mellitus (IDDM), also known as Type I, Juvenile onset, or ketosis prone diabetes. Another 16 million people have non-insulin dependent diabetes mellitus (NIDDM), also known as Type II or adult onset diabetes. Globally, the World Health Organization estimates the number of diabetics to exceed 80 million, many of whom are undiagnosed.
Acute complications from diabetes involve metabolic abnormalities such as hypoglycemia and ketoacidosis. Long term complications involve the blood vessels and tissues leading to retinopathy, stroke, myocardial infarction, heart failure, arterial occlusive diseases, nephropathy, kidney failure, and peripheral neuropathy. For example, diabetes produced blindness in over 39,000 people within the United States last year. About 25% of people with IDDM and 10% of the people with NIDDM have proliferative retinopathy within 15 years after diagnosis of diabetes. About 34% of IDDM and 19% of NIDDM have diabetic kidney disease within 15 years of diagnosis. Although all these diseases occur in the general population, they occur early and far more frequently, and progress more rapidly in diabetics.
There have been several studies which have proven that the occurrence or progression of complications of diabetes can be reduced substantially in IDDM diabetics if their blood sugars can be maintained at near normal levels. The Diabetes Control and Complications Trial (DCCT) was a nine year randomized prospective study involving more than 1,400 subjects. The DCCT compared the complication rate following standard IDDM management (mean glucose 195 mg/dl) versus tight control with frequent fingerstick blood testing and frequent insulin injections (mean glucose levels 155 mg/dl). Intensive therapy was shown to reduce the risk for development of retinopathy by 76% and reduce the progression of retinopathy by 54%. A smaller scale study known as the Oslo study followed 45 insulin dependent diabetics, randomized into three groups: multiple insulin injections, continuous subcutaneous insulin infusion (CSII), and conventional twice daily insulin injections. Near normoglycemia was obtained with CSII and multiple injections, but not with conventional therapy. After two years, the CSII and multiple injections groups showed little deterioration as measured by the number of microaneurisms and hemorrhages whereas the conventional therapy group showed significant deterioration.
Several observations can be made regarding these studies:
Although tight control reduces the secondary complication rate of diabetes significantly compared to loosely controlled diabetes, the risk of these complications is still several times higher than with the non-diabetic population.
Tight control involves a significant amount of inconvenience and pain, rendering such compliance an elusive goal for many, if not most diabetics. For example, to determine the appropriate insulin injection, a diabetic must measure his blood glucose at least five to six times daily which involves pricking one's fingers to draw blood and then measuring for blood glucose with a glucometer. For many patients, the drawing of blood is painful and inconvenient, in fact substantially more painful and inconvenient than the insulin injection.
Both studies pointed to a significant (two to three times) increase in severe and at times symptomless hypoglycemia for patients under tight control versus those under conventional therapy. Severe hypoglycemia leads to loss of consciousness and at times even coma. In patients under tight control, the incidence of severe hypoglycemia ran 0.6 to 0.8 incidents per year whereas for patients under conventional therapy, the incidence ran 0.2 to 0.4 incidents per year. For this reason, a continuous or quasi-continuous sensor which can provide an alarm is desired.
The blood glucose levels with patients under a tight control regime has a mean value of 155 mg/dl and varies from a low of 120 mg/dl to a high of 190 mg/dl over the course of a day. These levels are still quite a bit higher than the glycemia of non-diabetics which have a mean glycemia of 110 mg/dl and a variance from 90 to 120 mg/dl over the course of a day. Although the DCCT indicates the desirability of even a further reduction of blood glucose, the risk of hypoglycemia mitigates against any further reduction.
It is believed that a system which can maintain blood sugars to true normal levels (90-120 mg/dl) could potentially eliminate the complications of diabetes. Such a system would have an insulin infusion pump and a glucose sensor. Neither pump nor sensor would require much interaction on the part of the patient and would certainly be painless. The pumps are already well developed. The missing link is a sensor which can continuously measure blood sugar, is either non-invasive or implantable, and is accurate over a large range of physiological ranges.
The approaches taken by researchers to measure blood glucose consist of a variety of techniques, both optical and chemical. A variety of researchers have attempted implantable chemical sensors, but these sensor seem to invariably fail for the reasons outlined above. U.S. Pat. No. 5,353,792 (Lubbers et al.) discloses a variation on the chemical sensor which uses "optically excitable and readable indicating substances", one of which could presumably interact with glucose. The drawback to this approach is the same as other chemical techniques, namely the substances need to presumably interact directly with the constituent to be measured and therefore can potentially be depleted with time, or alternatively, the substances become blocked from interaction with the constituent due to encapsulation tissue. Another variation to the Lubbers et al. approach are affinity sensors based on fiber optics, described in Schultz, J. S. et al., "Affinity Sensor: A New Technique for Developing Implantable Sensors for Glucose and Other Metabolites," Diabetes Care, Vol. 5, No. 3, pp. 243, May-June 1982; and Mansouri, S. et al., Bio/technology, Vol. 2, pp. 385, 1984. These sensors also suffer from long term reduction in sensitivity.
The optical techniques also include a variety of approaches. Most of the approaches attempted have been non-invasive, transcutaneous means utilizing infrared spectroscopy. Infrared spectroscopy is based on the absorption of infrared light. The amount of absorption is dependent upon the concentration and light pathlength through the fluid being measured. Each chemical constituent has its own unique absorption spectra, depending upon the weight of each atom and strength of each molecular bond in a molecule. In theory, given enough signal to noise, one should be able to determine precisely the presence and concentration of each chemical constituent in a fluid, such as blood. Transcutaneous infrared spectroscopic techniques suffer from variability in optical coupling, poor signal to noise, and excessive artifacts. No device utilizing such techniques has yet been shown to work reliably. One technique disclosed in U.S. patent application Ser. No. 08/500,388, filed Jul. 6, 1995, entitled "IMPLANTABLE SENSOR AND SYSTEM FOR MEASUREMENT AND CONTROL OF BLOOD CONSTITUENT LEVELS," partially solved the coupling and signal to noise problem by implanting the sensor, as opposed to using it transcutaneously. A more detailed analysis of these two approaches is discussed below.
Several other optical approaches have also been attempted. U.S. Pat. No. 4,704,029 (Van Heuvelen) discloses an implantable device in which the concentration of glucose is inferred by a measurement of the refractive index of blood by an optical device in direct contact with blood. This device has many drawbacks, including the need for the device to have direct contact with blood. U.S. Pat. No. 5,209,231 (Cote et al.) discloses a somewhat different approach which is to measure the rotation of a plane of polarized light through blood or another body fluid. This technique and others like it use a very small rotation (millidegrees) and hence produce a very small signal, making the method very sensitive to scattering, movement, and pathlength variability.
As mentioned earlier, although in theory, given enough signal to noise, one should be able to determine the concentration of the constituents through infrared spectroscopy, in practice, such determinations have been shown to be very challenging. Measurement of glucose, in particular has been shown to be very difficult, even on an in vitro basis. The reasons are several fold:
(1) The body tissue and blood in particular are primarily composed of water. Water has a very strong intrinsic absorption in the infrared (IR) region, particularly in the mid IR region. The strong absorption by water severely reduces the signal to noise ratio, unless pathlengths are kept quite small. In the mid and near IR regions, pathlengths must be down to approximately 25 um or 1000 um, respectively, to obtain an acceptable signal to noise ratio.
(2) The concentrations of the constituents are low compared to that of water. The spectra of the various constituents in blood and other body fluids tend to overlap with one another and that of water, and almost all of the concentrations of constituents vary over the physiological range. For example, in the measurement of blood glucose concentration, the measurement must be taken against a backdrop wherein the concentration of the other constituents is constantly changing and the spectra of the other constituents overlap that of glucose.
(3) In the near IR region, both positions of the peaks and intensity of the water spectra shift with temperature and pH, further complicating the measurement.
(4) Blood and other body tissues tend to scatter light substantially, further reducing the signal to noise ratio detected by a sensor and further adding variability.
Despite these difficulties, several researchers have been able to determine glucose and other constituent concentration with acceptable or near acceptable accuracy on an in vitro basis, using multivariate techniques for the analysis of the spectra. It should be emphasized that these measurements were done on an in vitro basis, with a state-of-the art spectrophotometer, with a well-optimized set-up, and generally with factors not possible to reproduce on an in vivo basis, (i.e., temperature stability, constant pathlength). In addition, these measurement typically required a large number of spectral points (&gt;100) to obtain good accurate predictions of the constituent concentration. Hence, to make these measurements on an in vivo basis, extraordinary measures must be taken to ensure that the signal to noise ratio is the same or better as the in vitro measurements, and that there are no added additional artifacts.
Given the difficulty with in vitro measurements, it should come as no surprise that the transcutaneous means have not worked. In a transcutaneous sensor, the light "sees" a far large number of variables than what is seen on an in vitro basis due to the interaction of light with skin, fat, bone, and the like. Sorting out the spectra becomes very difficult. In addition, the signal to noise ratio obtainable with such a means is significantly lower than in vitro measurements due to substantially poorer optical coupling, the presence of additional scattering tissues (e.g., skin), and absorption by tissue which may not contain glucose (e.g., fat). Finally, given the accuracy necessary in the spectra to obtain an accurate determination of the constituent concentration, excessive artifacts are apt to obscure such measurements.
Attempts were made to eliminate some of the problems related to transcutaneous infrared sensor by using an implantable blood glucose sensor described in U.S. patent application Ser. No. 08/500,388, filed Jul. 6, 1995, entitled "IMPLANTABLE SENSOR AND SYSTEM FOR MEASUREMENT AND CONTROL OF BLOOD CONSTITUENT LEVELS". For example, this sensor improved the signal to noise ratio by implanting the sensor, thereby eliminating some of the sources of optical loss. The sensor in this patent application consists of spatially separated pairs of infrared light sources and infrared sensitive detectors. Each source and detector pair is spaced so that light from the source passes through a blood vessel and is received by the detector. Each source outputs a different discrete narrow band of light. The significant spatial separation between each source/detector pair causes a significant spatial separation of the spectral lines output by the sources. Each detector thus "sees" a different spatial region of the blood vessel. Due to this fact and the dynamic nature of blood vessels, it is believed that the spectral information output from the detectors cannot be used to obtain sufficiently accurate blood glucose levels.
Furthermore, the measurement technique in the above-described patent application fails to correct for spectral artifacts due to scattering and absorption by the blood vessel wall and any other tissue that may be in the optical path between the output of each source and the input of the corresponding detector. In addition, the diameter of a blood vessel is neither constant over time, since a blood vessel bulges and collapses with each heartbeat, nor uniform in diameter. In addition, blood is not spatially homogeneous, so there can be significant variability in scattering from point to point. Pathlength variability in the measurement techniques described in the above identified patent application may thus be on the order of 1 part in 100 (in absorbtivity units), which is large enough to destroy the usefulness of the spectral information obtained therefrom.
Many of the problems discussed above also arise when measuring other body fluid constituents. In sum, there are considerable obstacles to obtaining accurate in vivo measurements of body fluid constituents. Despite a long-felt need, sensors and spectral analysis techniques heretofore have been inadequate for this task. The present invention fulfills such a need and provides both sensors and spectral analysis techniques which yield accurate in vivo measurements of body fluid constituents.